Most protein-based targeted therapies currently in use target molecular mechanisms but not disease sites such as monoclonal antibodies which bind to diseased cells or to T cells (as in the case of ipilimumab and the related CTLA-4 antagonist tremelimumab). However, engagement of these targets in normal tissues gives rise to adverse events with various degrees of severity depending on the molecular target. If the therapeutic agent induces autoimmune phenomena the toxicity not only leads to significant morbidity, but also often necessitates the administration of immunosuppressants (corticosteroids, TNF-a inhibitors) which interfere with therapeutic intent.
There is a substantial, unmet need in the clinic to develop targeted therapies with reduced side effects and enhanced efficacy. Often referred to as “magic bullets”, monoclonal antibodies (mAbs) preferentially target diseased tissue and are generally better tolerated than traditional chemotherapy. In most cases, therapeutic mAbs bind to an antigen that is ‘self’ but overexpressed in the tumor, such as the Erbb family members (e.g., EGFR, Her2). However, systemic administration of these mAbs, at therapeutic doses, leads the mAb to engage antigen expressed on normal tissues, and thus, can lead to serious adverse side effects. As an example, the mAbs cetuximab (Erbitux™) and trastuzumab (Herceptin™) that are currently used to treat neck and colon cancers and breast cancer, also give rise to acneiform skin eruptions, gastrointestinal irritation and cardiotoxicity. Serious side effects due to off-target effects have been also been observed with other mAbs, such as efalizumab (Raptiva™). Indeed, the adverse effects of efalizumab in treatment of psoriasis, recently resulted in efalizumab being withdrawn from the market due to the development of progressive multifocal leukoencephalopathy. Adverse side effects of mAbs in clinical use reduce the efficacy of these agents, cause additional, substantial costs related to monitoring these side effects, and ultimately reduce patients' quality of life. In fact, the psychological aspect of the severe skin rashes alone has led patients to discontinue cetuximab, an effective treatment approved for various epithelial malignancies. Thus, there is a need in the art for treatment options which avoid these and other adverse effects. Provided herein are solutions to these and other problems in the art.